T cells play a central role in the recognition and elimination of foreign pathogens. However, they also pose a potential danger to their host, in that many of the properties that make them effective mediators of the immune response can be turned inadvertently against host tissue. Not surprisingly, the immune system has evolved a variety of mechanisms to ensure that T cells target foreign microbes with remarkable fidelity and selectivity. If any of these mechanisms breakdown, different pathologies ranging from immuno-deficiencies to auto-immune disorders can develop. The T cell receptor, or TCR, plays a critical role in the immune response, principally because signals through the TCR help control the extent and duration of T cell activation. To ensure that T cells are not inappropriately activated, signaling pathways downstream of the TCR are subject to multiple levels of positive and negative regulation. Recently, we discovered two related proteins that negatively regulate TCR signaling, Suppressor of T Cell Receptor Signaling-1 and -2 (Sts-1 & Sts-2). T cells from mice that have been genetically engineered to no longer express Sts-1 and Sts-2 are dramatically hyper-responsive to TCR stimulation. The phenotype is accompanied by increased phosphorylation of the critical T cell tyrosine kinase Zap-70. Additionally, hyper-activation of signaling proteins downstream of the TCR, a marked increase in cytokine production by Sts-1/2-/- T cells, and increased susceptibility to autoimmunity in a mouse model of multiple sclerosis are observed. Research in the lab focuses on understanding the mechanism of action of the Sts proteins. Additional projects explore other aspects of TCR signaling.